Is platelet-rich plasma effective for osteoarthritis?

Ubilla, Diego; Anan�as, Joaqu�n; Ortiz-Mu�oz, Luis; Irarr�zaval, Sebasti�n

doi:10.5867/medwave.2018.03.7216

Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)

Medwave 2018 May-Jun;18(3):e7216 doi: 10.5867/medwave.2018.03.7216

Is platelet-rich plasma effective for osteoarthritis?

Diego Ubilla, Joaqu�n Anan�as, Luis Ortiz-Mu�oz, Sebasti�n Irarr�zaval

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Abstract

INTRODUCTION
Despite varied non-surgical alternatives for the treatment of osteoarthritis, many patients remain symptomatic. In the last decade, the use of intra-articular platelet-rich plasma (PRP) has been proposed as an option. However, there is controversy about its clinical benefit and safety.

METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

CONCLUSIONS
We identified twelve systematic reviews including four studies overall, of which all corresponded to randomized trials. We concluded that intra-articular injection of platelet-rich plasma might slightly decrease joint pain and improve patient satisfaction,vut it is not clear whether it has any effect on functionality because the certainty of the evidence is very low. As for the adverse effects, if they exist, they would be non-severe and self-limited.

Problem

Osteoarthritis is a highly prevalent condition and an important cause of consultation in both primary and secondary care. The persistence of its symptoms, particularly pain, leads patients to repeated consultation, generally looking for non-surgical alternatives.Platelet-rich plasma is a blood product prepared through the centrifugation of autologous blood to increase the concentration of platelets and therefore the level of growth factors. The regenerative and anti-inflammatory potential of platelet-rich plasma is being studied in multiple musculoskeletal conditions, including osteoarthritis. Additionally, adverse effects would be mild, mainly secondary to arthrocentesis. However, the costs associated to this intervention are substantial, so it is important to have a clear estimation of benefits and harms.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

Intra-articular injection of platelet-rich plasma might slightly decrease joint pain, and improve patient satisfaction, but the certainty of the evidence is low.
It is not clear whether it improves knee function, because the certainty of the evidence is very low.
Most patients probably do not experience adverse effects, and if they present them, these are not severe and self-limited.

About the body of evidence for this question

What is the evidence. See evidence matrix in Epistemonikos later	We found twelve systematic reviews [1],[2],[3],[4],[5], [6],[7],[8],[9],[10], [11],[12] that included four primary studies [13],[14],[15], [16], all corresponding to randomized trials.
What types of patients were included*	All of the trials focused on osteoarthritis of the knee. Average age of patients ranged between 50.1 and 56.4 years [13],[14],[15], [16]. The proportion of women was between 55.1 and 93.5 in the different trials.
What types of interventions were included*	The number of platelet-rich plasma injections was one or two [13], two [14] and three [15],[16]. The volume injected in each trial was 5 ml [16], 4 to 6 ml [14], between 3 to 8 ml [15] and 8 ml [13]. The platelet activating agent was calcium chloride in two trials [13],[16] and none in the rest of the trials [14], [15]. The platelet-rich plasma was centrifuged once [13], [15] or twice [14], [16]. The leukocyte concentration of the platelet-rich plasma was poor in two trials [13],[15] and rich in the other two [14],[16], depending on the concentration of leukocytes in the blood of the patient. All of the trials compared against placebo. Three of them used saline as placebo [13],[15,[16] and the fourth did not use intra-articular injections in the control group.
What types of outcomes were measured	The outcomes reported in the systematic reviews were pain (measured with WOMAC pain scale) [4],[5],[6],[10],[12], functionality (measured with WOMAC function scale) [4],[5],[6],[10], total WOMAC [3],[5],[6],[8],[10], patient satisfaction [5],[8] and adverse effects [3],[4],[5],[6],[10]. Follow-up was 6 months in three trials [13],[14],[16] and 12 months in one trial[15].

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of Findings

The information on the effects of platelet-rich plasma was based on three randomized trials that included 140 participants [13],[14],[15]. One trial did not contribute to the meta-analysis [16].

All the trials measured the outcomes pain (WOMAC), functionality (WOMAC) and adverse effects. Only one trial [13] reported patient satisfaction (48 participants).

The summary of findings is as follows:

Intra-articular injection of platelet-rich plasma might slightly decrease joint pain in patients with osteoarthritis, but the certainty of the evidence is low.
It is not clear whether an intra-articular injection of platelet-rich plasma improves knee functionality because the certainty of the evidence is very low.
Intra-articular injection of platelet-rich plasma probably improves patient satisfaction. The certainty of the evidence is low.
Most patients probably do not experience adverse effects, and if they present them, these are not severe, self-limited and directly related to the number of intra-articular injections. The certainty of this evidence is moderate.

Other considerations for decision-making

To whom this evidence does and does not apply

This review applies to adults with symptomatic osteoarthritis of the knee. Nevertheless, it seems reasonable to extrapolate the results of this review to other affected joints because the mechanism of action of the intervention are similar regardless of the affected joint.
On the other hand, the use of platelet-rich plasma is being discussed in other musculoskeletal conditions that were not included in this review. However, we think it is not reasonable to apply the results of this review to such conditions.
This evidence does not apply to patients with previous surgical treatment because the reviews did not include such population.

About the outcomes included in this summary

The outcomes included in this summary are those considered critical for decision-making by the authors of this summary and agree with the Core Outcome Measures in Effectiveness Trials (COMET) [21] which states that the most relevant outcomes in osteoarthritis are: joint pain, functionality, patient satisfaction, quality of life in relation to health, work situation, mortality, reoperation and hospital readmission.

Balance between benefits and risks, and certainty of the evidence

Although platelet-rich plasma injections reduce joint pain, it is not over the minimally important difference reported in the literature [19] so the clinical relevance is not clear. On the other hand, it might improve patient satisfaction, but is not clear whether it improves physical functionality because the certainty of the evidence is very low.
In terms of safety: three trials analyzed intra-articular platelet-rich plasma adverse effects [13],[14],[15]. One trial [13] described self-limiting adverse effects (days) and directly related them to the number of intra-articular injections. None of the other two trials [14],[15] described adverse effects neither in the intervention group nor in the control group, thus it was not possible to estimate the safety of the intervention.
Regarding the certainty of the evidence, it is low for pain because serious risk of bias and inconsistency. Something similar occurs with the outcome physical functionality, as the certainty of the evidence is very low due to serious risk of bias and very serious inconsistency. The certainty of the evidence for the outcome patient satisfaction is low since this is and indirect outcome and serious risk of bias was reported in the systematic reviews. For the adverse effects, the certainty of the evidence is moderate due to imprecision.

Resource considerations

Considering that obtaining platelet-rich-plasma requires personnel, infrastructure and time to extract blood and process it, it is a relatively expensive intervention for the patient.
Furthermore, if we add there are small benefits, the balance between costs and benefits is probably not favorable.

What would patients and their doctors think about this intervention

There is high expectations among patients respect this kind of interventions, given the current non-surgical treatments are mainly symptomatic and require multiple lifestyle changes.
Currently, most clinicians do not routinely suggest intra-articular platelet-rich plasma due to insufficient evidence about the benefits and the high economic costs.

Differences between this summary and other sources

The conclusion of our summary agrees with most reviews included in this summary in terms of the small benefits associated with pain reduction and functionality when comparing intra-articular injections of platelet-rich plasma against placebo [2],[3],[4],[5],[6],[7],[8],[9],[10],[11]. It must be taken into consideration that several reviews mentioned the poor methodology of the included studies and substantial heterogeneity in the intervention [3],[4],[5],[6],[7],[8],[9],[10],[11],[12]. It is concluded that more studies with better methodology and homogenization in the intervention are needed to improve the certainty of the evidence, until now insufficient [2],[3],[5],[7],[9],[11].
This summary agrees with the NICE guideline 2014 [22] for osteoarthritis, in which the use of intra-articular platelet-rich plasma as an alternative non-surgical treatment for knee osteoarthritis is not recommended.

Could this evidence change in the future?

The probability that the conclusions of this summary change with future research is high, due to the existing uncertainty of the evidence.
We searched in PROSPERO (International Prospective Register of Systematic Reviews) where we found eight ongoing reviews [23],[24],[25],[26],[27],[28],[29],[30] which could change the results of this summary in the future.
We searched in the International Clinical Trial Registry Platform of the World Health Organization and we found seven ongoing trials which could provide relevant information for our topic of interest [31],[32],[33],[34],[35],[36],[37].

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Platelet-rich plasma versus placebo for osteoarthritis

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

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